The present invention relates to the use of an enantiomer of xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol (mefloquine) as an anti-malarial.
Malaria is an infectious parasitic disease transmitted by mosquitoes. It is characterized by periodic fever and an enlarged spleen. Malaria affects some 200 million people a year. Malaria in humans is caused by 4 species of parasitic protozoa belonging to the genus Plasmodium. Of these, P. falciparum produces the severe disease while P. malariae, P. vivax and P. ovale cause milder forms.
Malaria is transmitted by infected female Anopheline mosquitoes. The Plasmodia parasite matures in the insect, and is then transferred when the mosquito bites a human. Inside the human, the parasite settles first in the liver, multiplies and then invades the red blood cells. This is when the symptoms of malaria become evident.
Despite numerous attempts at eradication, malaria remains a serious endemic disease in many areas of Africa, Latin America and Oceania, with a worldwide mortality rate of approximately 1 million per year (WHO Scientific Group on the Chemotherapy of Malaria 1990). One of the major factors contributing to the continued presence of malaria is the emergence of malaria parasites that are resistant to one or more anti-malarial compounds.
Mefloquine is an anti-malarial compound which is effective against strains of the Plasmodium parasite which have developed resistance to conventional anti-malarial agents (for a review of its antimalarial activity, pharmacokinetic properties and therapeutic efficacy, see Palmer et al, Drugs, 1993, 45, 430-475). However, mefloquine resistance has now been reported in a number of areas including areas of Thailand (see Palmer et al.). Nevertheless, mefloquine is still one of the most effective anti-malarial mono-therapies and its use has increased greatly. Recently, the drug has attracted considerable adverse publicity owing to the incidence of severe neuropsychiatric side-effects, e.g. depression, psychosis, panic attacks, generalised anxiety. Although central nervous system (CNS) side-effects had been reported previously (particularly from its use by the armed forces in tropical areas; Croft and World (Neuropsychiatric reactions with mefloquine chemoprophylaxis. Lancet, 1996, 347, 326); Gullahorn et al. (Anaesthesia emergence delerium after mefloauine prophylaxis. Lancet, 1993, 341, 632)), their incidence had been regarded as sufficiently low to be of little concern. However, the widespread use of the drug by holidaymakers has resulted in a greatly increased number of CNS side-effect reports. A recent study (Barrett et al. (Comparison of adverse events associated with use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: postal and telephone survey of travellers. (British Medical Journal, 1996, 313, 525-528), in which 3851 travellers taking prophylactic anti-malarial medication were surveyed, has confirmed that there is a significant excess of adverse neuropsychiatric events associated with mefloquine administration compared with an alternative prophylactic treatment (proguanil plus chloroquine).
Clinical reports indicate that mefloquine may be proconvulsant (Ruff et al. (Seizure associated with mefloquine for malaria prophylaxis. Med. J. Aust., 1994, 161, 453)), anxiogenic (Hennequin et al. (Severe psychiatric side effects observed during prophylaxis and treatment with mefloquine. Arch. Intern. Med., 1994, 154, 2360-2362)), induce vertigo and dizziness (Sowunmi et al. (Neuropsychiatric side effects of mefloquine in Africans. Trans. Roy. Soc. Trop. Med. Hyg., 1993, 87, 462-463)) and may have central anticholinergic actions (Speich and Heller (Central anticholinergic syndrome with the antimalarial drug mefloquine. N. Engl. J. Med., 1994, 331, 57-58)).
Mefloquine is a molecule having two asymmetric carbon atoms and is usually used clinically as a racemic mixture of erythro ((xc2x1) (R*,S*)) isomers. Both of the mefloquine enantiomers have been reported to be equally effective against Plasmodium falciparum (Basco et al. (In vitro activity of the enantiomers of mefioquine, halofantrine and enpiroline against Plasmodium falciparum. Br. J. clin. Pharmac., 1992, 33, 517-520)), although another study claimed that the (+)-enantiomer was more potent than the (xe2x88x92)-enantiomer by a factor of 1.69-1.81 (Karle et al. (Plasmodium falciparum: role of absolute stereochemistry in the antimalarial activity of synthetic amino alcohol antimalarial agents. Exp. Parasitol., 1993, 76, 345-351)).
Mefloquine hydrochloride was introduced to the market as an anti-malarial agent in 1985. There have been over 40 families of patent applications on mefloquine covering: the use of the compound for treating malaria and other parasitic diseases; various processes for its preparation; and different formulations. The compound and its preparation was first described by Ohnmacht et al. (J. Med. Chem. 1971, 14, 926) in 1971. A more detailed account of the stereochemistry, synthesis, and anti-malarial activity of the isomers of mefloquine is given by Carroll and Blackwell (J. Med. Chem. 1974, 17, 210-219) in 1974.
It has now been found that the (+)-(11R,2xe2x80x2S)-enantiomer of xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol is effective as an anti-malarial and has reduced side-effects compared to the racemic (xc2x1)-(R*,S*)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol. The structures of the (+)-(11R,2xe2x80x2S)-enantiomer and the (xe2x88x92)-(11S,2xe2x80x2R)-enantiomer of xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol are shown below. 
In particular, it has been found that the (xe2x88x92)-enantiomer of mefloquine binds to CNS adenosine receptors, while the (+)-enantiomer is without significant activity at this binding site. The blocking of central adenosine receptors by the (xe2x88x92)-enantiomer is believed to result in the neuropsychiatric symptoms associated with mefloquine.
According to the present invention there is provided use of (+)-(11R,2xe2x80x2S)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol or a pharmaceutically acceptable salt thereof substantially free of its (xe2x88x92)-enantiomer in the manufacture of a medicament having reduced side-effects compared to the racemic (xc2x1)-(R*,S*)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol for treating or preventing malaria.
According to a further aspect of the present invention there is provided a method of treating or preventing malaria with reduced side-effects compared to the racemic (xc2x1)-(R*,S*)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol comprising administration to a subject in need of such treatment an effective dose of (+)-(11R,2xe2x80x2S)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol or a pharmaceutically acceptable salt thereof substantially free of its (xe2x88x92)-enantiomer.
The present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject.
(+)-(11R,2xe2x80x2S)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol may be employed in the present invention in an admixture with one or more other anti-malarial drugs such as, for example, chloroquine, pyrimethamine, sulfadoxine, amodiaquine, quinine/quinidine, halofantrine, artemether/artesunate, tovaquone, proguanil, doxycycline and dapsone. Combination with pyrimethamine and sulfadoxine is particularly preferred. According to a further aspect of the invention, (+)-(11R,2xe2x80x2S)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol and the other anti-malarial drug(s) may be in separate formulations, for use simultaneously or sequentially.
The term xe2x80x9ca method for treating or preventing malariaxe2x80x9d as used herein, means relief from malaria, preventing or inhibiting infection by parasitic protozoa of the genus Plasmodium which cause malaria and clearance of parasitic protozoa.
The term xe2x80x9csubstantially free of its (xe2x88x92)-enantiomerxe2x80x9d, as used herein, means that the composition contains a greater proportion of (+)-(11R,2xe2x80x2S)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol in relation to (xe2x88x92)-(11S,2xe2x80x2R)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol. In a preferred embodiment of the present invention the term xe2x80x9csubstantially free of its (xe2x88x92)-enantiomerxe2x80x9d as used herein means that the composition contains at least 90% by weight of (+)-(11R,2xe2x80x2S)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol and 10% by weight or less of (xe2x88x92)-(11S,2xe2x80x2R)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol. In a further preferred embodiment, the term xe2x80x9csubstantially free of its (xe2x88x92)-enantiomerxe2x80x9d means that the composition contains at least 99% by weight of (+)-(11R,2xe2x80x2S)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol and 1% or less of (xe2x88x92)-(11S,2xe2x80x2R)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol. In another preferred embodiment, the term xe2x80x9csubstantially free of its (xe2x88x92)-enantiomerxe2x80x9d as used herein means that the composition contains 100% by weight of (+)-(11R,2xe2x80x2S)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol. The above percentages are based on the total amount of xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol present in the composition.
The term xe2x80x9creduced side-effectsxe2x80x9d, as used herein, means that the pharmaceutical compositions employed in the present invention allow treatment and prevention of malaria and cause less side-effects than the racemic (xc2x1)-(R*,S*)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol. In a preferred embodiment of the present invention the term xe2x80x9creduced side effectsxe2x80x9d, as used herein, means that the pharmaceutical compositions employed in the present invention allow treatment and prevention of malaria and cause substantially less side-effects than the racemic (xc2x1)-(R*,S*)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol. In a more preferred embodiment of the present invention the term xe2x80x9creduced side-effectsxe2x80x9d, as used herein, means that the pharmaceutical composition employed in the present invention allow treatment and prevention of malaria and cause substantially no side-effects. The side-effects that are reduced, preferably substantially reduced, and more preferably avoided, include neuropsychiatric side-effects such as depression, psychosis, irritability, aggressiveness, panic attacks and generalised anxiety; seizures; proconvulsant effects; agitation effects; vertigo; dizziness; and anticholinergic symptoms. Preferably, the pharmaceutical compositions employed in the present invention exhibit reduced, preferably substantially reduced, preferably eliminated side effects associated with purinergic receptor binding activity.
It has been found that the (xe2x88x92)-enantiomer binds strongly to the adenosine receptor, while the (+)-enantiomer exhibits only a weak binding interaction.
There is evidence that blockade of adenosine receptors can result in a number of neuropsychiatric symptoms including tremor, anxiety, panic, insomnia and convulsions.
Adenosine receptors represent a sub-class (P1) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. The main pharmacologically distinct adenosine receptor subtypes are known as A1, A2A, A2B (of high and low affinity) and A3. Recent studies on mice bred without the adenosine A2A receptor (Ledent et al., (Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2A receptor. Nature, 1997, 388, 674-678)) indicate that these animals are more aggressive and anxious as well as having higher blood pressure than normal mice.
The effects in humans and laboratory animals of the adenosine receptor antagonists of theophylline, an asthma drug, and caffeine are well documented. These two drugs have fairly weak in vitro affinities at adenosine receptors (Ki values: theophylline A1 8.5 xcexcM, A2A, 25 xcexcM; caffeine A1 29 xcexcM, A2A, 48 xcexcM) (Jacobson, K. A. and van Rhee, A. M. (Development of Selective Purinoceptor Agonists and Antagonists, in Purinergic Approaches in Experimental Therapeutics, K. A. Jacobson and M. Jarvis (Eds). John Wiley and Sons, Inc., New York, 1997., pp 101-128)).
Patients taking theophylline are warned that they should inform their physicians if they have a seizure disorder, which is not surprising in view of the seizure inducing potential of adenosine receptor antagonists. Overdose with xanthines can result in seizures that are particularly refractory to treatment with clinically useful anticonvulsants (Chu, C. K. (Caffeine and aminophylline induced seizures. Epilepsia 1981, 22, 85-94)).
Adenosine is thought to be the agent that causes seizure arrest in man (Knutsen, L. J. S. and Murray, T. Adenosine and ATP in Epilepsy. In xe2x80x9cPurinergic Approaches in Experimental Therapeuticsxe2x80x9d, K. A. Jacobson and M. Jarvis (Eds)., John Wiley and Sons, Inc., New York, 1997, pp 423-447), and experimental data from rodents indicates that blockade of adenosine A1 receptors by theophylline immediately prior to an ischaemic episode exacerbates neuronal damage (Rudolphi, K. A.; Keil, M.; Hinze, H. J. Effect of theophylline on ischemically induced hippocampal damage in Mongolian Gerbils:, a behavioral and histopathological study. J. Cereb. Blood Flow Metab. 1987, 7, 74-81).
Given the undesired CNS effects observed in mammals with the relatively weak adenosine receptor antagonists theophylline and caffeine documented in the scientific literature, it is undesirable to administer to normal human subjects a potent adenosine receptor antagonist.
According to the present invention the use of the (+)-enantiomer of mefloquine, substantially free of the (xe2x88x92)-enantiomer, is particularly preferred in the treatment of a subject who has consumed or is likely to consume any chemical compound which interacts with a purinergic receptor. Consumption of such a compound includes ingestion of such a compound in food or drink, and administration of a drug, for example for treatment or prophylaxis of a medical condition by any route of administration (such as, but not limited to, oral ingestion). Compounds which interact with purinergic receptors particularly include compounds which interact with adenosine receptors. Such compounds include caffeine, theobromine, theophylline, carbamazepine, papaverine and dipyridamole; particularly caffeine, theobromine, theophylline, carbamazepine and papaverine; more particularly, caffeine, theobromine, theophylline and carbamazepine; more particularly caffeine, theobromine and theophylline; more particularly caffeine and theobromine; most particularly caffeine. Compounds which interact with purinergic receptors also include ethanol.
According to a further aspect of the present invention, the use of the (+)-enantiomer of mefloquine, substantially free of the (xe2x88x92)-enantiomer, is particularly preferred in the treatment of a subject having, or at risk from, a medical condition related to a disorder of purinergic receptor function. Medical conditions related to purinergic receptor activity include conditions causing or caused by an imbalance in purinergic receptor activity and conditions for which the medication causes an imbalance in purinergic receptor activity. Such medical conditions include, for example, neuropsychiatric disorders, cardiovascular disorders, digestive disorders, bronchial disorders and erectile dysfunction. Neuropsychiatric disorders of the CNS include psychiatric disorders [such as depression and anxiety disorders (such as panic disorders)], sleep disorders and seizure disorders. Cardiovascular disorders, which may be diagnosed or undiagnosed, include ischaemic heart disease, arrhythmia and related disorders, congestive heart failure and cerebrovascular disease (including transient ischaemic attacks). Subjects having cardiovascular disorders (or cardiovascular system investigations) particularly include subjects undergoing treatment with a beta-blocker drug, vasodilator or nifedipine. Subjects having digestive disorders particularly include subjects undergoing treatment with proton pump inhibitors. Bronchial disorders particularly include asthma and chronic obstructive pulmonary disease. Subjects having bronchial disorders particularly include subjects undergoing treatment with theophylline.
The pharmaceutical compositions employed in the present invention comprise (+)-(11R,2xe2x80x2S)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol as an active ingredient or a pharmaceutically acceptable salt thereof and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients known to those skilled in the art, such as one or more other anti-malarial drugs such as, for example, chloroquine, pyrimethamine, sulfadoxine, amodiaquine, quinine/quinidine, halofantrine, artemether/artesunate, tovaquone, proguanil, doxycycline and dapsone. The term, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d, refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.
Since the compound employed in the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most particularly preferred is the hydrochloride salt.
Any suitable route of administration may be employed for providing the patient with an effective dosage of (+)-(11R,2xe2x80x2S)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol. For example, oral, rectal, parenteral (intravenous, intramuscular), transdermal, subcutaneous, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like. The most suitable route in any given case will depend on the severity of the condition being treated. The most preferred route of administration of the present invention is the oral route. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
In practical use, (+)-(11R,2xe2x80x2S)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (e.g. intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used in the case of oral solid preparations such as, for example, powders, capsules, and tablets, with the solid oral preparations being preferred over the liquid preparations. The most preferred solid oral preparation is tablets.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques.
In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; 4,687,660; and 4,769,027, the disclosures of which are hereby incorporated by reference.
Pharmaceutical compositions employed in the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays each containing a predetermined amount of the active ingredient as a powder or granules, a solution or a suspension in an aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
For example, a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.